Thromb Haemost 1991; 65(04): 369-373
DOI: 10.1055/s-0038-1648154
Original Article
Schattauer GmbH Stuttgart

Antithrombotic and Anticoagulant Activity of Depolymerized Fragment of the Glycosaminoglycan Extracted from Stichopus japonicus Selenka

Norihiko Suzuki
*   Taiho Pharmaceutical Co., Ltd, Tokushima, Japan
,
Kenji Kitazato
*   Taiho Pharmaceutical Co., Ltd, Tokushima, Japan
,
Junki Takamatsu
**   First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya, Japan
,
Hidehiko Saito
**   First Department of Internal Medicine, Nagoya University School of Medicine, Nagoya, Japan
› Author Affiliations
Further Information

Publication History

Received: 17 August 1990

Accepted after revision 06 December 1990

Publication Date:
02 July 2018 (online)

Summary

The antithrombotic and anticoagulant activities of depolymerized fragment (DHG-l) of glycosaminoglycan extracted from Stichopw japonicus Selenka (FGAG) were compared with those of unfractionated heparin (UFH) or low molecular weight heparin (LMWH). DHG-1 at more than 0.3 mg/kg i. v. significantly prevented death of mice treated with thrombin (800 U/kg i.u.). Under the same conditions, FGAG, UFH and LMWH significantly prevented death of mice at more than 0.3, 0.3 and 0.6 mg/kg i.v., respectively. In normal plasma, the concentration required to double the activated partial thromboplastin time (doubling APTT) of DHG-I, FGAG, LMWH and UFH were 12.0, 2.4, 5.8, and 1.2 μg/ml, respectively. In antithrombin III (AT Ill)-depleted plasma, doubling APTT of DHG-1, FGAG, and UFH were 11.3, 2.1, and 18.5 μg/ml, respectively. Prothrombin activation in contact-activated plasma was inhibited completely for 60 s at doubling APTT by all glycosaminoglycans used in this study. DHG-I, however, showed much less antithrombin activity than UFH as tested by thrombin clotting time in plasma and chromogenic assay in the presence of AT III. Moreover, DHG-1 showed much less inhibitory activity on factor Xa, factor IXa, and glass surface-induced factor IXa generation than UFH

These results suggested that DHG-1 is one of the promising antithrombotic agents with quite different anticoagulant property from UFH or LMWH.

 
  • References

  • 1 Rosenberg RD, Damus PS. The purification and mechanism of action of human antithrombin-heparin cofactor. J Biol Chem 1973; 248: 6490-6497
  • 2 Rosenberg RD, Rosenberg JS. Natural anticoagulant mechanisms. J Clin Invest 1984; 74: 1-6
  • 3 Carter CJ, Kelton JG, Hirsh J, Cerskus AL, Santos AV, Gent M. The relationship between the hemorrhagic and antithrombotic properties of low molecular weight heparin in rabbits. Blood 1982; 59: 1239-1245
  • 4 Andriuoli G, Mastacchi R, Barbanti M, Sarret M. Comparison of the antithrombotic and haemorrhagic effects of heparin and a new low molecular weight heparin in rats. Haemostasis 1985; 15: 324-340
  • 5 Carter CI, Kelton J, Hirsh J, Gent M. Relationship between the antithrombotic and anticoagulant effects of low molecular weight heparin. Thromb Res 1981; 2l: 169-174
  • 6 Thomas DP, Merton RE, Barrowcliffe TW, Thunberg L, Lindahl U. Effects of heparin oligosaccharides with high affinity for antithrombin III in experimental venous. thrombosis. Thromb Haemostas 1982; 47: 244-248
  • 7 Ofosu FA, Blajchman MA, Modi GJ, Smith LM, Buchanan MR, Hirsh J. The importance of thrombin inhibition for the expression of the anticoagulant activities of heparin, dermatan sulfate, low molecular weight heparin and pentosan polysulphate. Br J Haematol 1985; 60: 695-705
  • 8 Ofosu EA, Hirsh J, Esmon Cl, Modi GJ, Smith LM, Anvari N, Buchanan MR, Fenton JW, Blajchman MA. Unfractionated heparin inhibits thrombin-catalysed amplification reactions of coagulation more efficiently than those catalysed by factor Xa. Biochem J 1989; 257: 143-150
  • 9 Bdguin S, Lindhout I, Hemker HC. The mode of action of heparin in plasma. Thromb Haemostas 1988; 60: 457-462
  • 10 Pieters J, Lindout T. The limited importance of factor Xa inhibition to the anticoagulant property of heparin in thromboplastin-activated plasma. Blood 1988; 72: 2048-2052
  • 11 Fan HZ, Chen JD, Lin KZ. Isolation of an acidic mucopolysaccharide from Stichopus japonicus Selenka and some of its physical and chemical properties. Tho Hsueh Hsueh Pao 1980; 15: 263-270
  • 12 Li JZ, Bao CG, Chen GZ, Zhang GZ, Zhang ZF, Fan HZ, Chen J, Hao X. Preliminary study on the effect of acid mucopolysaccharide from Stichopus japonicus Selenka on hemostasis. Zhongyao Tongbao 1983; 8: 36-39
  • 13 Thkamatsu J, Saito H, Kamiya I, Muranaka X, Minami Y, Fan HZ. A new mucopolysaccharide from Stichopus japonicw (sea cucumber) and its anticoagulant properties. Thromb Haemostas 1987; 58: 379 Abstr
  • 14 Li JZ, Lian ECY. Aggregation of human platelets by acidic mucopolysaccharide extracted from Stichopus japonicus Selenka. Thromb Haemostas 1988; 59: 435-439
  • 15 Kumada I, Dittman WA, Majerus PW. A role for thrombomodulin in the pathogenesis of thrombin-induced thromboembolism in mice. Blood 1987; 71: 728-733
  • 16 Ofosu EA, Blajchman MA, Modi G, Cerskus AL, Hirsh J. Activation of factor X and prothrombin in antithrombin III depleted plasma: the effects of heparin. Thromb Res 1981; 23: 331-345
  • 17 Abildgaard U, Lie M, Odegard OR. Antithrombin (heparin cofactor) assay with new chromogenic substrates (5-2238 and chromozym TH). Thromb Res 1977; 11: 549-553
  • 18 Proctor PR, Rapaport SI. The partial thromboplastin time with kaolin. A simple screening test for first stage plasma clotting factor deficiencies. Am J Clin Pathol 1961 36. 212-219
  • 19 Thomas DR, Merton RE. A low molecular weight heparin compared with unfractionated heparin. Thromb Res 1982; 28: 343-350
  • 20 Eggleton CA, Barrowcliffe TW, Merton RE, Thomas DP. In vitro and in vivo studies of the anti-Xa activity of heparin. Thromb Res 1981; 34: 319-328
  • 21 Ofosu FA, Smith LM, Anvari N, Blajchman MA. An approach to assigning in vitro potency to unfractionated and low molecular weight heparins based on the inhibition of prothrombin activation and catalysis of thrombin inhibition. Thromb Haemostas 1988; 60: 193-198
  • 22 Ouchterlony O. Handbook of Experimental Immunology. Weir DM. ed Blackwell Scientific; Oxford: 1967: 676
  • 23 Poon M-C, Saito H, Kopman WJ. A unique precipitating auto-antibody against plasma thromboplastin antecedent associated with multiple apparent plasma clotting factor deficiencies in a patient with systemic lupus erythematosus. Blood 1984; 63: 1309-1317
  • 24 Buchanan MR, Boneu B, Ofosu I, Hirsh J. The relative importance of thrombin inhibition and factor Xa inhibition to the antithrombotic effects of heparin. Blood 1985; 65: 198-201
  • 25 Tollefsen DM, Perska CA, Monafo WJ. Activation of heparin cofactor II by dermatan sulfate. J Biol Chem 1983; 258: 6713-6716
  • 26 Ofosu Fa, Sie P, Modi GJ, Fernandes I, Buchanan MR, Blajchman MA, Boneu B, Hirsh J. The inhibition of thrombin-dependent positive-feedback reactions is critical to the expression of the anticoagulant effect of heparin. Biochem J 1987; 243: 579-588
  • 27 Wagenvoord R, Hendrix H, Soria C, Hernker HC. Localization of the inhibitory site(s) of pentosan polysulfate in blood coagulation. Thromb Haemostas 1988; 60: 220-225